The primary aim of this study is to compare the need for MV in the first 72 hours of life (excluding the transient tracheal intubation performed for surfactant administration) in infants born at 25+0 to 28+6 weeks’ gestation who received the SLI maneuver in the delivery room or not.
This will be an unblinded multicenter randomized trial of SLI versus noSLI in infants born at 25+0 to 28+6 weeks’ gestation.
Inborn infants satisfying the following inclusion criteria will be eligible to participate in the study:
Born at 25+0 to 28+6 weeks’ gestation (and)
Parental consent has been obtained.
Presence of major congenital malformations.
Inherited disorders of metabolism.
Primary outcome measure
The primary endpoint of this study will be the need for MV within the first 72 hours of life. Therefore, we will consider SLI a success if MV is not required and a failure if the infant needs MV. The need for MV is defined later under ‘Criteria for starting MV’.
We have chosen the need for MV during the first 72 hours of life as our primary outcome measure to maintain similarity with the main previous trial conducted on this issue .
Secondary outcome measures
Need for conventional or high frequency modes of ventilation in the first 3 hours of life.
Highest FiO2 and oxygentherapy duration.
Duration of NCPAP, need and duration of bi-level nasal continuous positive airway pressure (BiPAP) and NIMV.
Need and duration of conventional MV (synchronized intermittent mechanical ventilation (SIMV), synchronized intermittent positive pressure ventilation (SIPPV), pressure support ventilation (PSV) with or without with volume guarantee (VG)) or high frequency ventilation (HFV).
Duration of hospitalization.
Highest mean airway pressure (MAP) during MV.
Need and number of doses of surfactant.
Occurrence of mild, moderate and severe bronchopulmonary dysplasia (BPD) .
Other collected data
The following data will be recorded for each infant: gestational age (GA), birth weight (BW), sex, Apgar score at 5 minutes, antenatal steroid treatment, CRIB II score , occurrence of pneumothorax, patent ductus arteriosus (PDA) and need of surgical closure, grade 3 to 4 intraventricular hemorrhage (IVH) , periventricular leukoma-lacia (PVL) , grade >2 retinopathy of prematurity (ROPand ROP requiring surgery , necrotizing enterocolitis (NEC) , sepsis , length of stay in neonatal intensive care unit (NICU) and hospital, and mortality. Patients will be discharged from the NICU to a lower level of care when they no longer need respiratory assistance other than oxygentherapy and central venous catheters.
We hypothesize that SLI maneuver might decrease the need for MV during the first 72 hours of life from 35% to 20%. We calculated that 138 newborns must be enrolled in each group to detect this difference as statistically significant with 80% power at a level of 0.05.
Written and oral information will, whenever possible, be offered to parents prior to the birth of their child if there is a risk that the mother will have a preterm delivery and the infant is likely to be eligible. Informed written consent will be signed by both the parents and sufficient time will be allowed for consent. Non-Italian speaking parents will only be asked for their consent if an adult interpreter is available. Trust interpreter and link worker services will be used to support involvement of participants whose first language is not Italian. A senior investigator will be available at all times to discuss concerns raised by parents or clinicians during the course of the trial.
A monthly accrual report of the study will be sent to participating centers.
Infants at each unit will be assigned to a block (1st block: gestational age from 25+0 to 26+6 weeks; 2nd block: gestational age from 27+0 to 28+6 weeks) and randomly assigned to a treatment group in 1:1 ratio using automatically generated sealed opaque envelopes, which will be prepared at Careggi University Hospital, Florence, Italy, and then distributed to participating centers. Block size will be concealed to investigators to ensure treatment balance between the two arms of the study.
The study will not be blinded and the staff performing the study will also care for the infants later on. However, the decision to start MV will be made by clinicians other than the investigators involved in patient care and researchers assessing study end-points will be blinded to the nature of the study treatments.
To minimize bias, strict criteria and definitions will be maintained during the trial.
Infants in the SLI group will undergo the following approach. After oropharyngeal and nasal suctioning, pre-ssure-controlled (25 cmH2O) inflation will be sustained for 15 seconds, using a neonatal mask and a T-piece ventilator, followed by the delivery of 5 cmH2O NCPAP. Patients will be observed for the following 6 to 10 seconds to evaluate their cardio-respiratory function. If respiratory failure persists (that is, apnea and gasping) and/or the heart rate is >60 and <100 bpm despite NCPAP, the SLI maneuver (again 25 cmH2O for 15 seconds) will be repeated. If the heart rate remains >60 and <100 bpm after the second SLI maneuver, the infant will be resuscitated following the current guidelines of the American Academy of Pediatrics (AAP) . Moreover, if the heart rate remains <60 bpm the infant will be resuscitated following the current guidelines of the AAP , and a second SLI maneuver will be repeated when the heart rate increases to >60 and <100 bpm. Infants in the control group will be treated with delivery of 5 cmH2O NCPAP and will be assisted following the guidelines of the AAP .
All enrolled infants will be transferred to the NICU in NCPAP (PEEP at 5 cmH2O).
Neonatal care will be started with FiO2 of 0.21 to 0.40 in both the groups, in agreement with the local protocols. Respiratory support in the delivery room will be given using the same T-piece ventilator (Neopuff Infant T-Piece Resuscitator, Fisher & Paykel, Auckland, New Zealand), which is a pressure-limited mechanical device that supplies consistent peak inspiratory pressure (PIP) and PEEP, and is capable of delivering sustained inflation . To avoid pressure leakage, a neonatal mask of appropriate size which adequately covers both the mouth and nostrils of infants will be used. The flow rate will be set at 8 to 10 l/min without changes during the resuscitation.
Criteria for starting MV
In the delivery room, infants will be started on MV if they have not reached the goal of 70% SpO2 by 5 minutes  and 85% by 10 minutes of life  with a heart rate >100 bpm, despite NCPAP at 5 cmH2O. In the NICU, infants will be started on MV when the pH is <7.20 with PaCO2>65 mmHg, PaO2<50 mmHg with FiO2 ≥0.50 after surfactant treatment, or if infants have frequent episodes of apnea (>4 episodes in 1 hour or >2 episodes requiring bag-and-mask ventilation), despite adequate NCPAP (5 to 7 cmH2O) delivery and oxygenation. MV will be set to maintain a PaCO2 of 55 to 65 mmHg and 88 to 95% SpO2.
Other aspects of respiratory support
To maintain an adequate SpO2, infants with an FiO2 ≥0.40 will be treated with surfactant (200 mg/kg Curosurf, ChiesiPharmaceuticals, Parma, Italy) followed by the reinstitution of NCPAP as soon as vital signs are satisfactory (intubation-surfactant-extubation (INSURE) strategy). All infants who will need MV will be treated with surfactant and will then be gradually weaned from it. Additional doses of surfactant (100 mg/kg) will be given to infants, also through the INSURE strategy, at the discretion of the attending neonatologist.
Infants will be extubated, after a loading dose of caffeine citrate (20 mg/kg), when they meet all of the following criteria: FiO2<0.40, PaCO2<65 mmHg with a pH >7.20, MAP <7 cmH2O, hemodynamic stability and the absence of clinically significant patent ductus arteriosus.
All collected data will be obtained from the clinical records. They will be recorded on electronic data sheets designed for this study. Data will be entered by the local principal investigator on a web-based electronic case record form. Access to the form will be password protected and participants will be identified by trial number only.
Clinical information will be collected at the following times:
1.At trial entry: eligibility, background information and randomization
2.Following randomization: all data above listed in ‘Primary outcome measure’, ‘Secondary outcome measures’ and ‘Other collected data’ sections.
Further information will be collected on expected serious adverse events (SAEs).
The primary efficacy analysis will be conducted on an intention-to-treat basis. Clinical characteristics of infants in the SLI and control groups will be described using mean values and SD, median value and range, or rate and percentage. Univariate statistical analysis will be performed using the Student’st-test for parametric continuous variables, the Wilcoxon rank-sum test for non-parametric continuous variables and the chi-square test for categorical variables. A P<0.05 will be considered statistically significant. SLI treatment and clinical characteristics which are most likely associated with the need for MV (gestational age, birth weight, antenatal steroids, CRIB score, INSURE procedure and hospital of birth) will be included in multiple logistic regression analysis to assess their independent role in predicting SLI success or failure. Effect estimates will be expressed as relative risk (RR) with profile likelihood-based 95% confidence limits.
An interim analysis is planned when 100 infants are enrolled (50 in each arm).
Duration of study
In this study, 272 infants will be recruited. The trial will terminate when the last recruited infant is discharged from hospital, or dies.